This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- NS-103: Demonstration of "Proof of Concept" for a New Therapeutic Approach in a Neurological Disease. Traumatic brain injury (TBI) is a significant health concern, affecting approximately 1.4 million people in the United States each year at a cost of $56 billion. Although significant research has been conducted to understand the pathophysiology of TBI, no pharmacological therapies are currently available to victims suffering from TBI. Posttraumatic epilepsy (PTE) occurs in over 30% of patients with moderate or severe TBI. Recent studies have implicated a novel injury mechanism identified as programmed necrosis (necroptosis) that merits consideration as a target for pharmacotherapy after TBI. Recently, a first in class small molecule inhibitor of necroptosis, TL14077 has been identified. We propose to evaluate the neuroprotective and anti- epileptic properties of this compound in a clinically relevant model of TBI. Recent work in our laboratory has shown that moderate fluid percussion (FP) brain injury reduces the threshold for seizures documented by both behavioral as well as electrophysiological changes when the convulsive agent PTZ is given to posttraumatic rats. Also, published findings reported that moderate TBI leads to long term alterations in sensorimotor as well as cognitive function. Thus, we hypothesize that treatment with an anti-necroptosis molecule (TL14077) will reduce the histopathological as well as functional consequences of this traumatic insult. In Aim 1, we will evaluate and optimize the dose-response efficacy and pharmokinetics of TL14077 by intravascular infusion. While previous studies have shown that this small molecule crosses the blood-brain barrier, pharmokinetic studies to document absorption, distribution, metabolism and elimination are required prior to the treatment studies. In Specific Aim 2, we will determine mechanisms by which inhibitors of necroptosis alter molecular mechanisms of traumatic injury in this model. Specifically, we will assess whether treatment with TL14077 will inhibit trauma-induced activation of receptor-interacting protein kinase 1 (RIPK1) activity in vulnerable brain regions. In Aim 3, we will assess the histopathological and cognitive consequences of TL14077 treatment following moderate FP brain injury. For these studies, histopathological characterization of contusion volume, selective neuronal damage, white matter pathology along with behavioral outcome measures including cognition will be evaluated. Finally, in Aim 4, the effects of TL14077 on PTE will be investigated. Seizure activity will be monitored by behavioral and electrophysiological indicators of neuronal excitation. The proposed studies are supported by investigators and medical professionals with expertise using the various experimental tools and outcome measures necessary to expand our repertoire of therapies available to patients suffering from TBI. Importantly, these preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future targeting acute TBI in humans. Traumatic brain injury (TBI) is a major cause of death and disability in the United States. There are currently no treatments to reverse the behavioral consequences of brain trauma. This grant will test whether a novel compound targeting a relatively new pathway of cell death after trauma will reduce the incidence of epilepsy and improve functional outcome in a clinically relevant animal model of TBI.